Structure and Function of Intrinsically Disordered Proteins

The existence and functioning of intrinsically disordered proteins (IDPs) challenge the classical structure-function paradigm that equates function with a well-defined 3D structure. Uncovering the disordered complement of proteomes and understanding their functioning can extend the structure-function paradigm to herald new breakthroughs in drug development. Structure and Function of Intrinsically Disordered Proteins thoroughly covers the history up to the latest developments in this field.

After examining the principles of protein structure, the classical paradigm, and the history of structural disorder, the book focuses on physical techniques for the identification and characterization of IDPs. It discusses proteomic and bioinformatic approaches and shows how IDPs behave under crowding conditions in living cells. The next several chapters describe the structure, correlating biological processes, and molecular mechanisms of IDPs. The author also explores the evolutionary advancement of structural disorder in proteomes and possible ways of extending the structure-function paradigm to encompass both ordered and disordered states of proteins. He concludes with discussions on the involvement of IDPs in various diseases and how to establish rational drug design through detailed characterization of IDPs.

Although drug discovery rates have leveled off, new insight generated by the study of IDPs may offer fresh strategies for drug development. This work illustrates how these proteins defy the structure-function paradigm and play important regulatory and signaling roles.

Peter Tompa is Group Leader in the Laboratory of Intrinsically Disordered Proteins, Institute of Enzymology, Biological Research Center at the Hungarian Academy of Sciences in Budapest.

Principles of Protein Structure and Function
Physical Forces That Shape Protein Structure
Primary Structure: Amino Acid Sequence
Protein-Coding Genes
Post-Translational Modifications of Amino Acids
Hierarchical Description of Structure
Folding of a Protein
Unfolding of a Protein: Lessons from Polymer Theory
The Limits of Global Descriptions of the Unfolded State
Databases of Proteins and Protein Structures
DisProt: The Database of Disordered Proteins
The Classical Structure-Function Paradigm
A Brief History of Protein Disorder
Can We Define Disorder?
The History of Disorder
So We Have Disordered Proteins
Indirect Techniques for Recognizing and Characterizing Protein Disorder
Resistance to Heat
Resistance to Chemical Denaturation
Unusual SDS-PAGE Mobility
Enhanced Proteolytic Sensitivity
Limited Proteolysis and Local Structure
Differential Scanning Calorimetry
Isothermal Titration Calorimetry
Chemical Cross-Linking
H/D Exchange
Hydrodynamic Techniques
Gel Filtration (Size-Exclusion) Chromatography
Dynamic Light Scattering
Analytical Ultracentrifugation
Small-Angle X-Ray Scattering
Pulsed-Field Gradient NMR
Spectroscopic Techniques for Characterizing Disorder
X-Ray Crystallography
Fluorescence Spectroscopy
Fourier-Transform Infrared Resonance Spectroscopy
Circular Dichroism
Raman Optical Activity Spectroscopy
Electron Paramagnetic Resonance Spectroscopy
Electron Microscopy
Atomic Force Microscopy
Nuclear Magnetic Resonance
Basic Principles
Global Characterization by NMR
Sequence-Specific Structural Information
Special Applications
Proteomic Approaches for the Identification of IDPs
Expectations and Limitations of Proteomic Studies
2DE-MS Identification of Proteins in Extracts Enriched for Disorder
Native/Urea 2DE Provides Direct Information on Disorder
IDPs under Conditions Approaching In Vivo
Macromolecular Crowding in the Cell
In Vitro Approaches to Mimicking Crowding Conditions
The State of IDPs In Vivo
Physiological Half-Life of IDPs: No Signs of Rapid Degradation
Indirect Considerations Underscoring Disorder of IDPs In Vivo
Prediction of Disorder
General Points
Propensity-Based Predictors
Machine-Learning Algorithms
Prediction Based on Interresidue Contacts
Prediction of Short and Long Regions of Disorder Separately
Combination of Predictors: Meta-Servers
Prediction of Functional Motifs in IDPs
Comparison of the Accuracy of Predictors: The CASP Experiment
A Better Target Prioritization in Structural Genomics
Structure of IDPs
Primary Structure of Disordered Proteins
Secondary Structure of Disordered Proteins
Ambiguity in Structure
Tertiary Structure: Global Features of IDP Structures
Dynamics of IDP Structure: The Time-Course of Fluctuations within the Ensemble
A Readout of Structure: The Hydrate Layer of IDPs
Biological Processes Enriched in Disorder
Biological Functions Enriched with Disorder
Disorder in Transcription/Transcription Regulation
Disorder in Signaling Proteins
Nucleic Acid-Containing Organelles
Disorder in RNA-Binding Proteins: Transcription and RNA Folding
Cytoskeletal Proteins
Disorder in Stress Proteins
Disorder and Metal Binding
Disorder and Enzyme Activity
Is There a Link between the Pattern of Disorder and Function?
Molecular Functions of Disordered Proteins
Entropic Chain Functions
Display Site Functions
Chaperone Functions
Effector Functions
Scavenger Functions
Assembler Functions
Prion Functions
Evolution and Prevalence of Disorder
Phylogenetic Distribution of Disorder
Fast Evolution of IDPs by Point Mutations
Fast Evolution of IDPs by Repeat Expansion
Fast Evolution and Functionality of Disordered Proteins
Structural Variability and Evolvability of New Functions
Extension of the Structure-Function Paradigm
Functions That Stem Directly from the Disordered State
Recognition Functions: Recognition by Short Motifs
Disorder-to-Order Transition in Recognition: Mechanistic and Thermodynamic Aspects
Recognition Functions: Uncoupling Specificity from Binding Strength
Implications of Disorder for the Kinetics of Interactions
Adaptability and Moonlighting
Nested Interfaces
Disorder in the Bound State: Fuzziness
Processivity of Binding
Sequence Independence in Recognition
Ultrasensitivity of Recognition
Signal Propagation in the Structural Ensemble of IDPs
Disorder and Alternative Splicing
Molecular Mimicry by a Disordered Region
Entropy Transfer in Chaperone Action
Structural Disorder and Disease
Structural Disorder and Cancer
Structural Disorder in Proteins Involved in Cardiovascular Diseases, Diabetes, and Autoimmune Diseases
Structural Disorder and Neurodegenerative Diseases
Systemic Amyloidoses
Common Themes in Amyloid Formation
Does Structural Disorder Pose a Danger?
Disorder in Pathogenic Organisms
Rational Drug Design Based on Protein Disorder
References